Critical role of tissue kallikrein in vessel formation and maturation: implications for therapeutic revascularization.

Abstract

OBJECTIVE:

Human Tissue Kallikrein (hKLK1) overexpression promotes an enduring neovascularization of ischemic tissue, yet the cellular mechanisms of hKLK1-induced arteriogenesis remain unknown. Furthermore, no previous study has compared the angiogenic potency of hKLK1, with its loss of function polymorphic variant, rs5515 (R53H), which possesses reduced kinin-forming activity.

METHODS AND RESULTS:

Here, we demonstrate that tissue kallikrein knockout mice (KLK1-/-) show impaired muscle neovascularization in response to hindlimb ischemia. Gene-transfer of wild-type Ad.hKLK1 but not Ad.R53H-hKLK1 was able to rescue this defect. Similarly, in the rat mesenteric assay, Ad.hKLK1 induced a mature neovasculature with increased vessel diameter through kinin-B2 receptor-mediated recruitment of pericytes and vascular smooth muscle cells, whereas Ad.R53H-hKLK1 was ineffective. Moreover, hKLK1 but not R53H-hKLK1 overexpression in the zebrafish induced endothelial precursor cell migration and vascular remodeling. Furthermore, Ad.hKLK1 activates metalloproteinase (MMP) activity in normoperfused muscle and fails to promote reparative neovascularization in ischemic MMP9-/- mice, whereas its proarteriogenic action was preserved in ApoE-/- mice, an atherosclerotic model of impaired angiogenesis.

CONCLUSIONS:

These results demonstrate the fundamental role of endogenous Tissue Kallikrein in vascular repair and provide novel information on the cellular and molecular mechanisms responsible for the robust arterialization induced by hKLK1 overexpression.

• Authors: Oliver A Stone, Christine Richer, Costanza Emanueli, Vincent van Weel, Paul H A Quax, Rajesh Katare, Nicolle Kraenkel, Paola Campagnolo, Luciola S Barcelos, Mauro Siragusa, Graciela B Sala-Newby, Danila Baldessari, Marina Mione, Marie P Vincent, Andrew V Benest, Ayman Al Haj Zen, Julien Gonzalez, David O Bates, Francois Alhenc-Gelas, Paolo Madeddu
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 29 Issue 5 Pg. 657-64 (May 2009) ISSN: 1524-4636 [Electronic] United States
• PMID: 19164804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tissue Kallikreins
• Matrix Metalloproteinase 9

Topics

• Animals
• Hindlimb (blood supply)
• Humans
• Ischemia (physiopathology)
• Kallikrein-Kinin System (physiology)
• Male
• Matrix Metalloproteinase 9 (physiology)
• Mice
• Mice, Knockout
• Neovascularization, Physiologic (physiology)
• Rats
• Splanchnic Circulation (physiology)
• Tissue Kallikreins (physiology)
• Wound Healing (physiology)
• Zebrafish